Dosing regimen for ppar-gamma activators

ABSTRACT

The present invention provides a method of treating a disease or condition, for example diabetes, with a PPAR-gamma activator comprising administration of the PPAR-gamma activator according to a dosing schedule which comprises a period of less than daily administration of the activator, for example alternate day administration.

FIELD OF THE INVENTION

This invention relates to methods for treating diseases or conditionswith PPAR-gamma activators. In particular, this invention relates todosing regimens for PPAR-gamma activators.

BACKGROUND

Peroxisome Proliferator Activated Receptors (PPARs) are orphan receptorsbelonging to the steroid/retinoid receptor superfamily ofligand-activated transcription factors. See, for example, Willson, T. M.and Wahli, W., Curr. Opin. Chem. Biol., (1997), Vol. 1, pp 235-241.Three mammalian PPARs have been identified which are termed PPAR-alpha,PPAR-gamma, and PPAR-delta. PPARs regulate expression of target genes bybinding to DNA response elements as heterodimers with the retinoid Xreceptor. These DNA response elements have been identified in theregulatory regions of a number of genes encoding proteins involved inglucose and lipid metabolism as well as energy balance. The biologicalrole of the PPARs in the regulation of lipid metabolism and storage hasbeen recently reviewed. See, for example, Spiegelman, B. M., Diabetes,(1998), Vol. 47, pp 507-514, Schoonjans, K., Martin, G., Staels, B., andAuwerx, J., Curr. Opin. Lipidol. (1997), Vol. 8, pp 159-166, and Brun,R. P., Kim, J. B., Hu, E., and Spiegelman, B. M., Curr. Opin. Lipidol.(1997), Vol. 8, pp 212-218, Way J. M., Harrington W. W., Brown K. K.,Gottschalk W. K., Sundseth S. S., Mansfield T. A., Ramachandran R. K.,Willson T. M. and Kliewer S. A., Endocrinology (2001), Vol. 142,pp1269-1277, Desvergne, B. Wahli, W Endocrinology Reviews (1999) 20(5):649-688).

PPAR-gamma activators are typically used to treat type 2 diabetes.PPAR-gamma activators enhance sensitivity to insulin-stimulated glucoseuptake and utilization, and thus reduce plasma glucose levels in humandiabetics and in rodent models of diabetes. This sustained plasmaglucose lowering effect, reflected clinically as a decrease in HbA1c, isreferred to as “glycemic control”, and represents the desiredanti-diabetic efficacy of this compound class. Additional benefits ofPPAR-gamma activator treatment in diabetic patients are reduction inserum triglyceride and free fatty acid levels, decrease in LDLcholesterol and an increase in HDL cholesterol.

However, the benefits of treatment with PPAR-gamma activators can beaccompanied by undesired side effects. A significant dose-limiting sideeffect of the currently marketed PPAR-gamma activators, observed indiabetic patients, is weight gain due to fluid retention. This fluidretention may lead to edema and, particularly in patients withpre-existing heart failure, the development of congestive symptoms,. Theincidence of edema may be increased if the PPAR-gamma activator) is usedin combination either with agents that stimulate insulin secretion, forexample sulfonylureas, or exogenously administered insulin. See, forexample, ACTOS, Physicians Desk Reference, (2001) 55^(th) edition, pp.3171-3175 or AVANDIA Physicians Desk Reference, (2001) 55^(th) edition,pp. 3871-3875.

Drug dosing regimens are typically designed to be convenient for thepatient, to promote compliance, to produce maximal benefit, and tominimize undesired side effects. For the vast majority of drugs, this isbest achieved through constant drug exposure at the lowest level thatproduces efficacy, and thus the optimal regimen is in most cases dailydrug administration. For drugs given daily, efficacy and side effectsare generally separable by total drug dosage, with side effectsoccurring at drug dosages that are higher by some multiple than thedosage producing the desired efficacy. Currently, PPAR-gamma activatorsare administered once or twice daily. See, for example ACTOS,(Physicians Desk Reference, (2001) 55^(th) edition, p 3175 or AVANDIA,Physicians Desk Reference, (2001) 55^(th) edition, p 3875.

In addition to daily drug dosing, there are examples of drugs that usedosing regimens in which the interval between drug doses is more than asingle day. While the interval may be two days (i.e. alternate-daydosing), or one week (i.e. once weekly dosing), or an extended period ofno dosing following a period of daily dosing, the underlying principlesare the same. In this discussion, any regimen intentionally comprisingan inter-dose interval greater than one day is referred to as less thandaily dosing.

Less than daily dosing is discussed extensively in therapeutic areas inwhich glucocorticoid therapy is a mainstay. See, for example, AxelrodL., Glucocorticoids, Textbook of Rheumatology, 4^(th) edition, vol 1, pp779-ff, (1986); Physicians Desk Reference, 48^(th) edition, section onDELTASONE, pp 2408-2409, (1994); Holland and Taylor, Glucocorticoids inclinical practice, J Family Prac 32: 512-519, (1991); and Hodson E M,Knight J R, Willis N S, and Craig J C, Corticosteroid therapy fornephrotic syndrome in children (Cochrane Review), The Cochrane Library,Issue 4, (2001).

For hormone replacement therapy, for treatment of menopausal disorders,estrogen has been administered by a variety of dosing regimens, oftengiven daily for several weeks, followed by one week of no dosage. Thisis intended to minimize stimulation of proliferation inestrogen-sensitive tissues, such as uterus, by partly mimicking thenormal endocrine physiology. See, for example The Pharmacological Basisof Therapeutics, (1996) 9^(th) edition, pp. 1422-1423.

Alendronate, used for prevention and treatment of osteoporosis, wasoriginally developed for daily dosing. Subsequently, for variousreasons, including minimization of esophagitis seen as a side effect,the drug was approved for once-a-week dosing. In this case, knowledge ofpharmacokinetics, specifically that the drug distributes only into bone,was used to predict that infrequent dosing would be fully efficacious,since bone is the target tissue for the drug. See, for exampleSchnitzer, T J, Update on Alendronate: Once-Weekly dosing. Expert OpinPharmacother 2: 1461-1472, (2001).

In addition to minimization of side effects, minimization of drug costis sometimes part of the rationale for alternate-day dosing. Fortreatment of hypercholesterolemia, it was recently reported thatlovastatin given as less than daily dosing was equally as efficacious aswhen given daily, and thus was a cost-effective method of treatment.See, for example Dennis, V C, Britton M L, Sirmans S M, Letassy N A,Freeman D A, The use of alternate-day lovastatin in hypercholesterolemicmen, Ann Pharmacother 31: 708-711, (1997).

BRIEF DESCRIPTION OF THE INVENTION

Briefly, in one aspect, the present invention provides a method oftreating a disease or condition, for example diabetes, with a PPAR-gammaactivator comprising administration of the PPAR-gamma activatoraccording to a dosing schedule that comprises at least one period ofless than daily dosing of the activator, for example alternate daydosing. The dosing regimen of this invention, as compared to dosingregimens comprising daily or twice daily administration of PPAR-gammaactivator, may result in no significant decrease in efficacy, forexample glycemic control, but with a significant decrease in undesiredeffects, for example fluid retention which can lead to weight gain,hemodilution, and edema. The dosing regimen of this invention may beused in conjunction with other treatments. For example, the PPAR-gammaactivator dosing regimen of this invention can be used in combinationwith either exogenous insulin or drugs that increase the secretion ofendogenous insulin.

DETAILED DESCRIPTION OF THE INVENTION

PPAR-gamma activators includes PPAR-gamma agonists. As used herein, a“PPAR-gamma activator” includes any compound that activates humanPPAR-gamma by any accepted assay, or any compound generally recognizedas a PPAR-gamma activator or agonist. Such PPAR-gamma activators may beactivators of more than one PPAR subtype. Preferred PPAR-gammaactivators include the thiazolidinediones (TZDs) known to be useful fortreating diabetes and also non-thiazolidinedione (non-TZDs) PPAR-gammaactivators such as those disclosed in U.S. Pat. No. 6,294,580.Particularly preferred TZDs include those currently marketed, such asrosiglitzone and pioglitazone. Particularly preferred non-TZDs includecompounds in development such as the GlaxoSmithKline compound GI262570(farglitazar).

As used herein “less than daily dosing” will be used to indicate anyintentional dosing regimen that comprises at least one period in whichthe frequency of dosing is less than daily, for example every other day,or which comprises at least one gap of at more than I day where there isno administration of the PPAR-gamma activator. In the case of dosingregimens that comprise a gap or day without administration, as usedherein such gaps or days without administration of the PPAR-gammaactivator must be preceded and followed by administration of activator.This is meant to include any dosing regimen comprising gaps in dosing ofmore than one day. For example, the dosing regimens of this inventioninclude regimens comprising 5 days with and 2 days withoutadministration of the activator, or 12 with and 2 without, or 19 withand 2 without, or 26 with and 2 without, or 11 with and 3 without, or 18with and 3 without, or 25 with and 3 without, or 10 with and 4 without,or 17 with and 4 without, or 24 on and 4 without, etc. This is trueregardless of the average number of doses per day. For example, twicedaily administration every other day would be less than daily dosing.The dosing regimen of this invention can include several days or weeksof daily or twice daily dosing followed by a period of less than dailydosing. As used herein a day with dosing or a day with administration ofactivator includes once, twice, or any number of doses on thatparticular day.

Preferred dosing regimens are those that comprise periods of every otherday or every third day or twice weekly dosing, or that comprise one ortwo or three consecutive days without administration. When thePPAR-gamma activator dosing regimen of this invention is used incombination with administration of either exogenous insulin or drugsthat increase the secretion of endogenous insulin, the insulin oradditional drug can be administered with a dosing regimen that is thesame as or different from the PPAR-gamma activator regimen. As usedherein “dosing” and “administration” are intended to be identical.

Experimental

Four animal studies were carried out regarding the effects of PPAR-gammaactivator treatment. The PPAR-gamma activator used in these experimentswas GI262570 (farglitazar), which may be prepared as described in U.S.Pat. No. 6,294,580. These four studies are described in detail below. Asused herein “bid” means twice daily.

Study 1:

Rat Model of PPAR-Gamma Activator Induced Fluid Retention/Edema

Normal Han Wistar female adult rats were housed in metabolic cages andorally dosed (8 mg/kg, bid) with PPAR-gamma activator or vehicle(PEG400, 1 ml/kg) for 21 days. Electrolyte and water balance, plasmavolume, hematocrit, and interstitial fluid volume were measured.Compared with vehicle treated control rats, rats treated with PPAR-gammaactivator showed a sustained increase in electrolyte and waterretention, ultimately resulting in a 6% increase in plasma volume and a6% decrease in hematocrit. In addition, there was a 50% increase ininterstitial fluid volume, correlating to an edematous state.

These results indicate that daily treatment with a PPAR-gamma activatorcaused sustained fluid retention and development of edema. As noted inthe background section above, this PPAR-gamma activator effect has alsobeen observed in human clinical studies.

Study 2:

Rat Model of PPAR-Gamma Activator Induced Cardiovascular Changes Leadingto Fluid Retention and Edema

Normal Han Wistar female adult rats were chronically instrumented formeasurement of cardiac output, blood pressure and total peripheralresistance and orally dosed (8 mg/kg, bid) with PPAR-gamma activator orvehicle (PEG400, 1 ml/kg) for 10 days. Data were collected for 7 daysprior to the start of dosing, for 10 days of dosing, and for 7 daysafter discontinuation of dosing. In rats treated with the PPAR-gammaactivator, total peripheral resistance decreased, and cardiac outputincreased, beginning within six hours after the initial dose, andreached steady state by treatment day four. When dosing wasdiscontinued, total peripheral resistance and cardiac output began toreturn toward control values within 24 hours, with full recovery afterfour days. The decrease in total peripheral resistance is believed to bethe initial pharmacodynamic effect of PPAR-gamma activators leading tofluid retention and edema.

Study 3:

Model of PPAR-Gamma Activator Induced Efficacy/Glycemic Control

Two glucose-matched groups (n=6/group) of Zucker Diabetic Fatty (ZDF)rats, 7-8 weeks of age, were treated with vehicle (n-methylglucamine,0.05M, 1 ml/kg, p.o.) or PPAR-gamma activator (5 mg/kg, bid). After fourweeks of treatment, all rats treated with PPAR-gamma activator werevolume expanded and two were overtly edematous, and PPAR-gamma activatordosing was discontinued. At the time dosing was discontinued, theaverage non-fasted plasma glucose was 154 mg/dl in PPAR-gamma agonisttreated rats compared to 464 mg/dl in the vehicle-treated controls. Thislevel of glycemic control was maintained despite discontinuation ofPPAR-gamma activator treatment for 10 days, at which time the averageplasma glucose in the rats previously treated with PPAR-gamma activatorwas 175 mg/dl, compared to 462 mg/dl in vehicle-treated controls. Incontrast to the sustained glycemic control, the fluid volume expansionwas not sustained, as evidenced by the finding that the hematocritreturned from and end-of-treatment value of 47% to a control value or52% within 3 days.

Taking the hematocrit response as indicative of the expanded plasmavolume resulting from increased fluid and electrolyte retention, thesedata suggested that the beneficial pharmacodynamic effect of PPAR-gammaactivators (glycemic control) was of longer duration than thepharmacodynamic effects leading to salt and water retention. In otherwords, the results above show that the time course for thecardiovascular changes that lead to the reversal of the fluid retentionand edema was shorter than the duration of glycemic control afterdiscontinuation of dosing. This time-differential finding suggests thatit may be possible to achieve glucose control without fluid retentionduring PPAR-gamma activator therapy by decreasing the frequency ofdosing from daily to some form of less than daily dosing. The resultsalso show that the mechanism of PPAR-gamma induced fluid retention,namely the fall in total peripheral resistance, begins within six hoursof the first dose, a vascular effect that will stimulate salt and waterretention. Knowledge of the on and off rate of the primary vascular andsecondary renal effects suggests an appropriate dosing regimen. This wastested in Study 4 below.

Study 4:

Less Than Daily Dosing with PPAR-gamma Activator

Three groups of 8 plasma glucose-matched ZDF rats with non-fastedglucose values greater than 250 mg/dl were dosed with PPAR-gammaactivator. During the study plasma glucose and serum albumin weremeasured weekly, HbA1c was measured every other week, and heart weightsand body weights were measured terminally. Reduction of plasma glucoseand HbA1c are markers for anti-diabetic efficacy (glycemic control).Decreased plasma albumin concentration is a marker for plasma volumeexpansion or hemodilution. The heart weight-to-body weight ratio is amarker for increased cardiac output secondary to volume expansion.

All three groups were initially dosed with PPAR-gamma activator for oneweek at 5 mg/kg twice daily, in order to achieve glycemic control asshown by plasma glucose less than 250 mg/dl, and volume expansion asshown by reduced serum albumin.

After the initial week of dosing, the mean non-fasted plasma glucose forall rats was 138 mg/dl (compared to pre-treatment values of 321 mg/dl)and the serum albumin concentration was 3.5 gm/dl (compared topre-treatment value of 3.8 gm/dl). Following the first week one group(Group BID) was continued on the daily dosing regimen while the othertwo were moved to less than daily dosing. Group BID continued to bedosed at 5 mg/kg twice daily, Group MWF was dosed at 10 mg/kg per daythree times weekly (Monday/Wednesday/Friday), and Group MF was dosed at10 mg/kg per day twice weekly (Monday/Friday). These three dosingregimens were continued for five weeks.

Because this study was designed to determine whether fluid retentioncould be eliminated while glycemic control was maintained, only animalsdemonstrating continued glycemic control (non-fasted plasma glucose lessthan 250 mg/dl) were evaluated. All 8 rats in the BID group met thiscriterion, as did 6 in the MWF group and 5 in the MF group. The data issummarized in Tables 1, 2, and 3, and only includes the 19 rats thatexhibited glycemic control.

The data summarized in FIG. 1 show that during the last two weeks ofstudy, plasma glucose (in the 11 responding rats) was slightly higher inthe MWF and MF dose groups, but still well below pre-dosing levels, thusdemonstrating that all three dosing regimens resulted in glycemiccontrol in these animals.

As further evidence of this, HbA_(1c) values, which indicate averageplasma glucose integrated over time, were below 6% for all 19 animals.The data summarized in FIG. 2 show that serum albumin concentration wassimilarly decreased in all rats after the first week of dosing,indicating that plasma volume was increased. By day 14 of reducedfrequency dosing, the MWF and MF group values returned to and remainedat pre-treatment baseline values, while the BID group value remainedbelow the pre-treatment baseline value throughout dosing.

The data summarized in FIG. 3 show that the terminal heart weight tobody weight ratio for the BID group was increased by 13% compared to theMWF and MF dose groups. Heart weight/body weight ratio values from theliterature for normal rats of the same body weight average 0.23 with arange of 0.19-0.25 as the 95% confidence limits. Thus, both the MWF andMF dose group heart weight/body weight ratios were within normal ranges,while that for the BID dose group was increased beyond the normal range.This indicates that the alternate day dosing regimens prevented thefluid retention that occurs with daily dosing, and thus prevented theincrease in cardiac output that leads to increased heart weight.

The results of the studies described above demonstrate that, withalternate day dosing regimens, it is possible to achieve the desiredglycemic control with PPAR-gamma activators, without producing undesiredfluid retention and edema.

1. Method of treating a disease or condition with a PPAR-gamma activatorcomprising administration of the PPAR-gamma activator according to adosing schedule which comprises a period of less than daily dosing. 2.The method of claim 1 wherein the dosing schedule comprises at least oneday in which there is no administration of the PPAR-gamma activator. 3.The method of claim 1 wherein the dosing schedule comprises 2consecutive days in with there is no administration of the PPAR-gammaactivator.
 4. The method of claim 1 wherein the dosing schedulecomprises a period selected from the group consisting of administrationof the activator on alternate days, administration of the activator ononly two days per week, and administration of the activator every thirdday.
 5. The method of claim 1 wherein the PPAR-gamma activator isrosiglitazone or farglitazar.
 6. The method of claim 1 wherein thedisease or condition is selected from the group consisting ofhyperglycaemia, dyslipidemia, Type II diabetes, Type I diabetes,hypertriglyceridemia, syndrome X, insulin resistance, heart failure,diabetic dyslipidemia, hyperlipidemia, hypercholesteremia, hypertension,obesity, anorexia bulimia, anorexia nervosa, and cardiovascular disease,including ischemia-reperfusion injury and atherosclerosis, cancer,Alzheimer's disease or other cognitive disorders.
 7. The method of claim6 wherein the disease or condition is diabetes.
 8. The method of claim 7further comprising administration of an agent that stimulates insulinsecretion or insulin.
 9. The method of claim 8 wherein said agent isselected from the group consisting of sulfonyureas, metformin,glucophage